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Tolerance refers to the reduction in or loss of drug efficacy caused by long-term administration and indicated by the pharmacological changes to the right of the dose-response curve, the development and degree of which depend on the drug interactions with the opioid receptors, drug dose, and frequency of administration [15]

doi: 10.1038/s41586-019-1912-x 253 MortonDLThompsonJFCochranAJMozzilloNNiewegOERosesDFet al